1. fMRI Network Analysis and Resting State Studies a. Functional brain networks associated with risk-reward conflict in alcohol dependence Deficits in behavioral control, heightened impulsivity, and aberrant reward evaluation are all hallmarks of alcohol dependence that may contribute to impaired decision-making and risky behavior. The goal of this study was to investigate if regional activations underlying risk-reward conflict processes operate in functional networks. Thirty-four healthy controls and 16 alcohol dependent participants were scanned while presented with an experimental paradigm in which reward accrual and risk of penalty simultaneously increased. Participants were prompted to decide when to stop the reward accrual period. If the participant failed to end the trial before an undisclosed time the trial would bust and participants would lose the money earned from the current trial (low penalty) or the money from both the current trial and an equivalent amount from prior earnings (high penalty). The study also included a motor control trial (no reward) and a guaranteed reward trial. We found that three networks had significantly different activation in ADPs compared to controls. ADPs demonstrated increased connectivity in the executive control network (ECN) in the no reward and guaranteed reward trial types. ADPs showed blunted connectivity in salience networks involving the insula in the penalty trials. The ECN, previously linked to approach behaviors, exhibited amplified activity in the ADPs. This finding may relate to the heightened inclination to approach rewards common in the ADPs. In contrast, two networks involving the insula showed diminished activity in the ADPs. These findings corroborate past fMRI studies linking altered insula recruitment to addiction (manuscript in preparation). b. Resting State Connectivity i. Resting State functional connectivity - In this study we used Probabilistic Independent Component Analysis (PICA) on resting-state fMRI data obtained from a sample of healthy controls and inpatient alcohol dependent participants. We found that, compared to healthy controls, ADPs have increased within-network functional connectivity (FC) in the salience (SN), default-mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN), and amygdala-striatum (ASN) networks. ADPs also demonstrated increased between-network FC among the LECN, ASN and SN. These findings add evidence to the concept of altered within-network FC in alcohol dependent populations and also highlight the role of between-network FC in the pathophysiology of this patient population (Zhu et al., 2015). ii. Resting state functional connectivity of Anterior Insula. There is a growing evidence that insula plays a major role in addiction because of its function in interoceptive awareness, craving, and regulating emotionally influenced decision-making. We conducted this study using a seed-based approach, with the anterior insula as seed region. In comparison to healthy controls, the ADPs left anterior insula showed higher connectivity with right nucleus accumbens and regions of anterior cingulate. The right anterior insula showed higher connectivity with some of the same regions of anterior cingulate. Both insula and anterior cingulate are the regions in Salience network and involved in conflict-processing and error-detection (manuscript in preparation). iii. Resting state functional connectivity and genetics - In collaboration with Dr. Lohoff, we examined the behavioral and neuronal consequences of inter-individual difference in the presynaptic monoamine transporter (VMAT1) resting-state functional connectivity in alcoholics and healthy. Five minutes of closed-eyes resting state fMRI were collected from 140 individuals (72 controls and 68 ADPs). When compared to participants with the major allele, participants with the minor allele 136Ile showed significantly decreased FC in the DMN, PFCN, and ECN in ADPs only. The findings implicate the functional VMAT1 Thr136Ile variant in the neuroadaptations in ADPs and suggest a possible protective effect of the minor allele. The data suggests the functional variant as a possible new target for investigation of pathophysiology in ADPs (Zhu et al., in press). iv. Classification of Alcohol Dependence - We have applied machine-learning approaches to identify both within-network and between-network connectivity features that may be used as phenotypes to explain addiction in a multivariate fashion and that is predictive of (able to classify) alcohol dependence. Five minutes of closed-eyes resting state fMRI were collected from 92 individuals (46 controls and 46 ADPs). PICA was used to extract brain functional networks and their corresponding time-courses. Both within-network connectivity and between-network connectivity for each pair of networks were used as features. We applied random forest for pattern classification. The results showed that in classifying the samples to alcohol dependent participants and healthy control participants within-networks contribute the most. In this classification, the within-networks connectivity of Executive Control Network (ECN) and Reward Network (RN) contributed the most to accuracy of the classification. The between-network connectivity between RN and Default Mode Network (DMN), RN and ECN contributed the most to the classifier. Our results suggest that connectivity within the ECNs and RN are informative in predicting alcohol dependence diagnosis. These results suggest that machine learning-based approaches to classifying rs-FC offer a valuable alternative technique to understanding large-scale differences in addiction-related neurobiology (manuscript in preparation). 2. Structural Connectivity a. Diffusion Tensor Imaging Over the past four years, SBEI has also continued investigation of the structural underpinnings associated with alcohol dependence. We have examined the contribution of structural connectivity and the potential damage to white matter integrity to various compromised functions in alcohol use disorders using MR diffusion tenor imaging in 55 alcohol dependent patients and 58 healthy controls. In this study we utilized Tract-based Spatial Statistics and Connectometry. When comparing alcohol dependent patients with healthy controls we found interruptions in white matter massages to Supramarginal and inferior parietal gyri, which are areas related to good decision-making, language processing, and lack of empathy towards others; in superior temporal gyrus which is implicated in perception of emotional and facial stimuli and more importantly social cognition processes and in pathway to amygdala; as well as compromised fiber tracts, mostly on the left side of the brain, in passages to several regions including tracts to inferior frontal gyrus, which is known to be involved in behavioral inhibition and risk aversion (manuscript in preparation).